Lyophilization Syringe

ABSTRACT

Herein described are an assembly, apparatus, and method for lyophilization that utilizes a thermal block made from a conductive material, the block having multiple wells designed and dimensioned to receive containers carrying material to be lyophilized in situ. In preferred embodiments, a vented silicone pad covers the wells and secures the containers therein, and a similarly vented rigid plate in turn secures the silicone pad by fastening it to the thermal block. The assembly can be turned up to 90 degrees resulting in the turning of the containers from an upright position to a horizontal position, a position in which the distance through which sublimation must progress is drastically reduced so as to greatly enhance the efficiency of the lyophilization process.

I. PRIORITY

This application is a continuation of U.S. patent Ser. No. 18/066,108filed Dec. 14, 2022, which, in turn, is both a continuation-in-part ofU.S. patent application Ser. No. 17/588,349 filed Jan. 31, 2022 (whichissued as U.S. Pat. No. 11,536,512 on Dec. 27, 2022) and claims thebenefit of U.S. Provisional Application No. 63/474,132 filed Jul. 21,2022. The contents of these prior applications are hereby incorporatedby reference in their entirety.

II. TECHNICAL FIELD

The present invention relates to an assembly, apparatus and method forlyophilization. More particularly, the present invention relates to animproved assembly, apparatus and method for lyophilization of materials,particularly biological preparations including but not limited topharmaceuticals.

III. BACKGROUND OF THE PRESENT INVENTION

Freeze-drying, also known as lyophilization or cryodessication, is awell-known low temperature dehydration process universally acceptedacross multiple industries, including the chemical, pharmaceutical, andfood industries, that involves freezing a product (typically a liquid orwater-containing product), lowering pressure, then removing the ice viasublimation. This stands in contrast to the more conventionaldehydration processes that use heat to evaporate water in its liquidform.

Primary applications of lyophilization include biological (e.g.,bacteria and yeasts), biomedical (e.g., surgical transplants,pharmaceuticals), food processing (e.g., coffee) and preservation. Dueto the low temperature used in processing, the quality of thelyophilized product upon rehydration is excellent. Lyophilized productsfurther offer certain advantages such as extended shelf-life andstability which makes the process popular.

The process of lyophilization has been widely adopted in thepharmaceutical industry and more specifically in biologicalpreparations. Most biological preparations are temperature sensitive andhave a short shelf life. Other biological formulations, such asvaccines, need to be stored at temperatures as low as −70 to −80° C. orbelow. Indeed, a first iteration of the Pfizer-BioNTech COVID-19 vaccinerequired storage at ultra-low freezing temperatures, about −100 degreesFahrenheit, a temperature that falls well below standard freezercapabilities.

Equipment to maintain such low temperature for storage andtransportation is expensive and often not available. Lyophilizedformulations, however, have less temperature stringency and cantherefore be stored at temperatures above 0° C. that can be easilymaintained in normal refrigerators. Additionally, the lyophilizedformulations have a long shelf life, and the dosage remains withinpharmaceutical specifications for a longer time. The lyophilized dosageforms can be readily solubilized for easy and dependable administration.This improved stability, extended shelf life, and minimal refrigerationand monitoring requirements during transit and storage makelyophilization processes exceptionally well-suited for preserving andstoring biological preparations.

Lyophilization has traditionally been performed in containers, such asvials and ampoules. Lyophilization can also be performed directly in asyringe, with the lyophilized medication being stored in the samesyringe. However, convection and radiation, the most common methods forheat transfer in the lyophilization process, are slow processes thattend to be associated with non-uniform heating during batchlyophilization. For example, under typical radiation condition, unevenheat transfer gives rise to higher sublimation rates in those vials orsyringes located on the periphery of an array (e.g., at the front andsides of the array) as compared to those more centrally disposed. Towit, it is quite common for a batch to have fully mature hard productcake at the edges of the pan while the center of the batch is soft andraw. This lack of uniformity is highly problematic.

However, pharmaceuticals lyophilized directly in a dispensing syringeare highly preferred for their stability and long shelf life, as well astheir convenience. For example, at patient administration, a diluent canbe added to the pre-filled syringe for reconstitution of the lyophilizedproduct, thereby allowing the medication to be administered from thelyophilized syringe directly to the patient. Such in-situ lyophilizationalso reduces labor as compared to preparation of a patient injectionfrom a vial. In addition, product waste is reduced, while a moreaccurate dosage is administered. As vaccines provided in multidose vialswane in demand and the single-dose vaccine becomes more preferred,lyophilized medicines are uniquely positioned by not requiring theburden of ultra-low temperature freezing for shipment, storage, andproduct monitoring by expensive temperature sensing systems requiringremote 24/7 surveillance on the product.

Considering the benefits afforded by lyophilization as well as itsincreasing use in industry, there remains a constant desire,particularly in the pharmaceutical arts, to make the lyophilizationprocess more efficient by reducing the product lyophilization cycletimeline, increasing throughput making the process more economical.

IV. SUMMARY OF THE PRESENT INVENTION

Bearing in mind the above, the present invention offers an improvementover the state of the art by utilizing an apparatus and methodologywhereby lyophilization cycles can be shortened using novel designtechniques and materials.

Accordingly, it is a primary objective of the present invention toprovide a lyophilization assembly, apparatus and method that imparts ashorter lyophilization cycle timeline. It is another objective of thepresent invention that the lyophilization method be efficient. It isstill another objective of the present invention to provide a readilyscalable lyophilization apparatus and method. It is yet a furtherobjective of the present invention to provide a lyophilization assembly,apparatus and process that affords uniformity in all units of alyophilization batch.

Embodiments of the present invention that meet one or more the foregoingobjectives are summarized below. However, this simplified summary of oneor more embodiments of the present invention is intended to provide abasic understanding of such embodiments and thus is not meant to be anextensive overview of all contemplated embodiments. Nor is the followingsummary intended to identify key or critical elements of all embodimentsnor to delineate the scope of any or all embodiments. Rather, its solepurpose is to present some concepts of one or more embodiments in asimplified form as a prelude to the more detailed description that ispresented later.

In a first aspect, the present invention provides a lyophilizationassembly, apparatus and method having optimized lyophilization cycletimelines and thereby shortened into more favorable timelines, whereinthe lyophilization assembly includes a thermal block made from heatconductive material, preferably a material having high heatconductivity. In preferred embodiments, the thermal block includes aplurality of identical wells evenly arrayed across multiple rows,wherein the wells are configured to receive containers forlyophilization that contain products to be lyophilized.

In preferred embodiments, the wells are sized and shaped to closelyapproximate the dimensions of the corresponding containers, moreparticularly to cause deformation to a polymeric container placedtherein. In this manner, substantial contact is created between theouter walls of each container and the interior walls of its respectivewell which, in turn, allows heat to be evenly transferred at a fasterrate from the block to the containers and finally to the product in thecontainers.

In certain embodiments, both the wells and the containers aresquare-shaped, such that the square-shaped containers can closely fitinto the square-shaped wells. In other embodiments, both the wells andcontainers exhibit coordinating rounded profiles. In either case, thecontainers preferably take the form of a syringe barrel in which theproduct can be lyophilized directly.

Thus, in view of the above, it is an objective of the present inventionto provide a lyophilization syringe suitable for in situ lyophilizationof an initial product as well as reconstitution and dispensing of alyophilized product, wherein the syringe is composed (i) an elongatecentral barrel having a hollow bore configured to retain the initialproduct to be lyophilized and optionally provided with a wide radialflange at its proximal end; (ii) an open distal tip configured to engagea hypodermic needle assembly and optionally sealed by a distal stopper,such as luer cap, and (iii) an open proximal end configured to receiveand/or include a sealing piston and dispensing plunger, wherein saidcentral barrel has a polygonal cross-section, preferably a substantiallysquare cross-section characterized by four elongate side panels thatoptionally bow outward to form a convex exterior surface. Thelyophilization syringe may optionally further include a venting capremovably mounted to the open proximal end, whereby when said cap ispartially inserted into the proximal opening, a passage for gaseousoutflow from the container interior is formed, thereby providing anescape path for outgassing during the lyophilization process, furtherwherein the passage is closed when the cap is fully inserted into theproximal opening, such that the lyophilized product is sealed within thecontainer interior.

A further objective of the present invention is to provide alyophilization apparatus composed of:

-   -   a. a thermal block made from a heat conductive material,        optionally of metal, preferably of aluminum, characterized by a        top side, a bottom side, and a medial thickness extending        therebetween, wherein the block is provided with a plurality of        uniform wells, each of which is configured to receive a single        container, wherein the wells are arranged on said top side and        of a predetermined depth, optionally extending through the        medial thickness of the block such that each well is comprised        of a proximal opening disposed in the top side of said block and        a distal exit in the bottom side of the block; and    -   b. one or more containers, each of which is optionally        fabricated from a resilient polymer, preferably polypropylene,        wherein each container optionally takes the form of a vial, an        ampoule or a dispensing syringe, characterized by deformable        lateral walls defining an exterior surface, a hollow interior        configured to retain a product in its initial and lyophilized        forms, and a proximal opening;    -   wherein associated wells and containers are analogously sized        and shaped, whereby insertion of a container into its respective        well causes said lateral walls to deform, thereby directly        compressing the exterior surface of the container is against an        inner wall of the respective well.

In preferred embodiments, each container takes the form of a dispensingsyringe characterized (i) an elongate central barrel having a hollowbore configured to retain the product to be lyophilized, (ii) an opendistal tip configured to engage a hypodermic needle assembly, whereineach open distal tip is optionally sealed by a distal stopper andpreferably takes the form of a Luer taper configured to receive a distalstopper in the form of a Luer cap, and (iii) a proximal opening isconfigured to receive a sealing piston and dispensing plunger. Inparticularly preferred embodiments, the central barrel (a) has asubstantially square cross-section characterized by four elongate sidepanels, wherein each of the side panels optionally bow outward to form aconvex exterior surface that compresses against the inner wall of itsrespective well; and (b) optionally includes a wide radial flange thatrests against the proximal opening of its corresponding well so as toprevent vertical displacement of the syringe from the thermal block.

It is yet another objective of the present invention to provide alyophilization assembly comprised of the above lyophilization apparatus,optionally including the above lyophilization syringe, in which one ormore containers are each inserted into a respective well, in combinationwith a means for alternatively sealing and venting the respectiveinteriors of the one or more containers. In one embodiment, the meansfor alternatively sealing and venting the respective interiors of theone or more containers takes the form of a series of container caps,each of which is removably mounted to the proximal opening of acorresponding container, whereby when the cap is partially inserted intothe proximal opening, a passage for gaseous outflow from the containerinterior is formed, thereby providing an escape path for outgassingduring the lyophilization process, further wherein the passage is closedwhen the cap is fully inserted into the proximal opening, such that thelyophilized product is sealed within the container interior.Alternatively, the means for alternatively sealing and venting therespective interiors of the one or more containers make take the form of(a) a sealing member configured to cover the top side of the block andthe plurality of wells, the sealing member, optionally a silicone pad,having a first venting mechanism, optionally a series of aperturesconfigured to allow vapors to escape from the one or more containers,and (b) a plate, optionally of a rigid material such as metal, glass, orcarbon fiber filled polymeric composite, configured to secure thesealing member to the block, the plate having a second ventingmechanism, optionally in the form of a series of perforations configuredto allow the vapors received through the first mechanism to escape. Inpreferred embodiments, the plate perforations align with the siliconepad apertures but are offset from the axis of the respective proximalopenings so as to prevent fluid leakage.

In a preferred embodiment, the lyophilization assembly further includesan ejector plate to assist in the removal of the one or more containersfrom the thermal block, the ejector plate being composed of a planarbase having a plurality of vertical portions protruding therefrom,wherein the vertical portions are identical in number and spatialorientation to that of the plurality of wells such that moving theblock-container apparatus downward onto the vertical portions causes thecontainers to be dislodged from their respective wells.

Finally, it is yet a further objective to provide a method forlyophilization that utilized the aforementioned lyophilization assemblyto lyophilize a product in situ, wherein the method includes the stepsof:

-   -   a. placing one or more containers in an upright position into        the plurality of wells, wherein the proximal openings face up;    -   b. via the respective proximal openings, filling each container        with a product to be lyophilized;    -   c. engaging the means for sealing and venting the respective        interiors of the one or more containers so as to allow vapors to        escape from the one or more containers while preventing product        from leaking;    -   d. optionally rotating the lyophilization assembly from the        vertical configuration, wherein the proximal openings face up,        to the horizontal, wherein proximal openings face sideways, so        as to enhance the efficiency of the lyophilization process; and    -   e. applying heat to the thermal block until all water is removed        from the product to be lyophilized.

These and other objectives and features of the invention will becomemore fully apparent when the following detailed description is read inconjunction with the accompanying figures and examples. However, it isto be understood that both the foregoing summary of the invention andthe following detailed description are of a preferred embodiment, andnot restrictive of the invention or other alternate embodiments of theinvention. In particular, while the invention is described herein withreference to a number of specific embodiments, it will be appreciatedthat the description is illustrative of the invention and is notconstructed as limiting of the invention. Indeed, various modificationsand applications will readily occur to those who are skilled in the art,without departing from the spirit and the scope of the invention, asdescribed by the appended claims. In addition, those skilled in the artwill recognize that one or more aspects of this invention can meetcertain objectives, while one or more other aspects can meet certainother objectives. Moreover, each objective may not apply equally, in allits respects, to every aspect of this invention. As such, the precedingobjectives and subsequently presented preferred embodiments can beviewed in the alternative with respect to any one aspect of thisinvention.

V. BRIEF DESCRIPTION OF THE FIGURES

Various aspects and applications of the present invention will becomeapparent to the skilled artisan upon consideration of the briefdescription of figures and the detailed description of the presentinvention and its preferred embodiments that follows:

FIG. 1 is a distal perspective view of a syringe barrel formed inaccordance with the principles of the present invention.

FIG. 2 is a proximal perspective view of the objects of FIG. 1 .

FIG. 3 is a plan view of the objects of FIG. 1 .

FIG. 4 is a side elevational view of the objects of FIG. 1 .

FIG. 5 is a proximal end view of the objects of FIG. 1 .

FIG. 6 is a sectional view of the objects of FIG. 3 at location A-A.

FIG. 7 is an expanded sectional view of the objects of FIG. 4 atlocation B-B.

FIG. 8 is a perspective view of a cap for a syringe barrel formed inaccordance with the principles of the present invention.

FIG. 9 is a plan view of the objects of FIG. 8 .

FIG. 10 is a distal axial view of the objects of FIG. 8 .

FIG. 11 is a side elevational view of the objects of FIG. 8 .

FIG. 12 is an expanded sectional view of the objects of FIG. 9 atlocation A-A.

FIG. 13 is a perspective view of a distal stopper for a syringe barrelof the present invention.

FIG. 14 is a side elevational view of the objects of FIG. 13 .

FIG. 15 is an axial view of the objects of FIG. 13 .

FIG. 16 is a distal perspective view of a syringe barrel assembly of thepresent in which the cap of FIG. 8 and distal stopper of FIG. 13 aremounted to the syringe barrel of FIG. 1 , and wherein the cap is in afirst, venting position.

FIG. 17 is a proximal perspective view of the objects of FIG. 16 .

FIG. 18 is a plan view of the objects of FIG. 16 .

FIG. 19 is a side elevational view of the objects of FIG. 16 .

FIG. 20 is a sectional view of the objects of FIG. 18 at location A-A.

FIG. 21 is an expanded view of the objects of FIG. 20 at location A.

FIG. 22 is an expanded view of the objects of FIG. 20 at location B.

FIG. 23 is a plan view of the objects of FIG. 16 wherein the cap is in asecond, sealing position.

FIG. 24 is a side elevational view of the objects of FIG. 23

FIG. 25 is a sectional view of the objects of FIG. 23 at location A-A.

FIG. 26 is an expanded view of the objects of FIG. 25 at location A.

FIG. 27 depicts a syringe barrel of the present invention wherein afluid to be lyophilized has been placed in a first step of alyophilization method of the present invention.

FIG. 28 is a sectional view of the objects of FIG. 27 at location A-A.

FIG. 29 depicts a second step in the method of the present invention inwhich the cap is place on the syringe barrel as in FIG. 16 .

FIG. 30 is a sectional view of the objects of FIG. 29 at location A-A.

FIG. 31 is a perspective view of a thermal block of the presentinvention wherein are formed multiple wells for receiving syringebarrels of the present invention.

FIG. 32 is a plan view of the objects of FIG. 31 .

FIG. 33 is an axial end view of the objects of FIG. 31 .

FIG. 34 is a plan view of a segment of the block of FIG. 31 containing asingle well, hereinafter used to depict subsequent steps of alyophilizing method of the present invention.

FIG. 35 is a side elevational view of the objects of FIG. 34 .

FIG. 36 is a perspective view of the objects of FIG. 34 .

FIG. 37 is an expanded sectional view of the objects of FIG. 35 atlocation A-A.

FIG. 38 depicts a third step in lyophilization methods of the presentinvention in which the syringe barrel with cap is placed in the well ofthe thermal block of FIG. 31 .

FIG. 39 is a sectional view of the objects of FIG. 38 at location A-A.

FIG. 40 is an expanded sectional view of the objects of FIG. 38 atlocation B-B.

FIG. 41 is an expanded view of the objects of FIG. 39 at location A.

FIG. 42 depicts a fourth step in a lyophilization method of the presentinvention in which the block and syringe barrel are rotated so that thesyringe barrel axis is horizontal and the fluid is in a liquid state.

FIG. 43 is a sectional view of the objects of FIG. 42 at location A-A.

FIG. 44 depicts a fifth step in a lyophilization method of the presentinvention in which the liquid has been fully lyophilized.

FIG. 45 depicts a sixth step in the method of the present inventionwherein the syringe barrel and block are returned to a verticalposition.

FIG. 46 depicts a seventh step in which the cap is inserted into thesyringe barrel to its second, sealing position.

FIG. 47 is an expanded view of the objects of FIG. 46 at location A.

FIG. 48 depicts an ejector plate for use with the thermal block of FIG.31 .

FIG. 49 is a plan view of a segment of the ejector plate of FIG. 48containing a single upright, hereinafter used to depict subsequent stepsof a lyophilizing method of the present invention.

FIG. 50 is a perspective view of the objects of FIG. 49 .

FIG. 51 is a sectional view of the objects of FIG. 49 at location A-A.

FIG. 52 is an upper perspective view of an eighth step in the method ofthe present invention wherein the block and syringe barrel arepositioned on the upright of the ejector segment of FIG. 49 .

FIG. 53 is a lower perspective view of the objects of FIG. 52 .

FIG. 54 is a side elevational view of the objects of FIG. 52 .

FIG. 55 is a sectional view of the objects of FIG. 54 at location A-A.

FIG. 56 is a perspective view of a ninth step in the method of thisinvention in which the syringe barrel is partially ejected from theblock segment.

FIG. 57 is a side elevational view of the objects of FIG. 56 .

FIG. 58 is a sectional view of the objects of FIG. 57 at location A-A.

FIG. 59 depicts a syringe barrel of the present invention withlyophilized material formed using methods of the present invention.

FIG. 60 is a sectional view of the objects of FIG. 59 at location A-A.

FIG. 61 is a perspective view of an exploded assembly used in analternate embodiment lyophilization method of the present invention.

FIG. 62 depicts a second syringe barrel of the present inventioncontaining fluid for lyophilization is inserted into a thermal blocksegment in a first step of a lyophilization method of the presentinvention.

FIG. 63 is a side elevational view of the objects of FIG. 62 .

FIG. 64 is a sectional view of the objects of FIG. 63 at location A-A.

FIG. 65 depicts a second step of the method wherein a gasket and plateare positioned on the thermal block segment.

FIG. 66 is a sectional view of the objects of FIG. 65 at location A-A.

FIG. 67 depicts a third step in which the objects of FIG. 65 arereoriented in a horizontal position.

FIG. 68 depicts a fourth step in which the fluid has been fullylyophilized.

FIG. 69 depicts a fifth step in which the syringe barrel and block havebeen returned to a vertical position.

FIG. 70 depicts a sixth step in which the plate and gasket have beenremoved.

FIG. 71 depicts a seventh step in the lyophilization method in which aplunger is inserted into the syringe barrel until the plunger seal sealsthe material within the plunger barrel.

FIG. 72 is a sectional view of the objects of FIG. 71 at location A.

FIG. 73 depicts an eight step in which the sealed syringe is partiallyejected from the thermal block segment.

FIG. 74 is a sectional view of the objects of FIG. 73 at location A-A.

FIG. 75 depicts a ninth step in which the distal stopper is removed andthe plunger is advanced with the distal end elevated.

FIG. 76 is a sectional view of the objects of FIG. 75 at location A-A.

FIG. 77 depicts a syringe of the present invention wherein is formedlyophilized material using methods of the present invention.

FIG. 78 is a sectional view of the objects of FIG. 77 at location A-A.

FIG. 79 is a side elevational view of an alternate embodiment of thethermal block of the present invention, wherein are formed multiplerounded wells for receiving syringe barrels of the present invention.

VI. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

While various embodiments are henceforth described, the followingdescription is intended to be exemplary, rather than limiting, and itwill be apparent to those of ordinary skill in the art that many moreembodiments and implementations are possible that are within the scopeof the embodiments. Likewise, although many possible combinations offeatures are shown in the accompanying figures and discussed in thisdetailed description hereinbelow, many other combinations of thedisclosed features are possible. As such, any feature or element of anyembodiment may be used in combination with or substituted for any otherfeature or element in any other embodiment unless specificallyrestricted.

Although methods and materials similar or equivalent to those describedherein can be used in the practice or testing of embodiments of thepresent invention, the preferred methods and materials are nowdescribed. However, it is to be understood that this invention is notlimited to the particular sizes, shapes, dimensions, materials,methodologies, protocols, etc. described herein, as these may vary inaccordance with routine experimentation and optimization. It is also tobe understood that the terminology used in the description is for thepurpose of describing the particular versions or embodiments only, andis not intended to limit the scope of the present invention which willbe limited only by the appended claims. Accordingly, unless otherwisedefined, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich the present invention belongs. However, in case of conflict, thepresent specification, including definitions below, will control. Thus,in the context of the present invention:

The words “a”, “an”, and “the” as used herein mean “at least one” unlessotherwise specifically indicated. Thus, for example, reference to an“opening” is a reference to one or more openings and equivalents thereofknown to those skilled in the art, and so forth.

The term “proximal” as used herein refers to that end or portion of adevice that is situated closest to the user of the device, farthest awayfrom the active or operative end of a device. In the context of thepresent invention, the proximal end of a syringe of the presentinvention includes the sealing cap, plunger and finger grip portions.

The term “distal” as used herein refers to that end or portion of adevice that is situated farthest away from the user of the device,closest to the operative end. In the context of the present invention,the distal end of a syringe of the present invention refers the outputend adapted to receive a needle and/or stopper element.

The terms “lengthwise” and “axial” are used interchangeably herein torefer to the direction relating to or parallel with the longitudinalaxis of a device.

The term “transverse” as used herein refers to the direction lying orextending across or perpendicular to the longitudinal axis of a device.

The term “lateral” pertains to the side and as used herein, refers tomotion, movement, or materials that are situated at, proceeding from, ordirected to a side of a device.

The term “medial” pertains to the middle, and as used herein, refers tomotion, movement or materials that are situated in the middle, inparticular situated near the median plane or the midline of the deviceor subset component thereof.

The terms “tube” and “tubular” are interchangeably used herein to referto a generally round, long, hollow component having at least one centralopening often referred to as a “lumen”.

The present invention interchangeably makes reference to “containers”and “product containers” designed to carry an initial product to belyophilized (generally in liquid form), withstand the temperatures andpressures associated with lyophilization, and store the subsequentlyophilized product until called for use. In the context of the presentinvention, such containers are preferably fabricated from a deformablepolymeric material, such as polypropylene. More particularly, such as inthe exemplary embodiments identified above and described in detailbelow, the product container is preferably the barrel of a syringe.However, it will be readily understood that the container need not be asyringe barrel but rather may take the form of a vial, bottle, ampoule,syringe, tube, or other suitable vessel or receptacle.

In the context of the present invention, the terms “syringe”, “syringebody”, and “syringe barrel” are used interchangeably to refer to aspecialized lyophilized product container, namely dispensing devicecomprised of a central hollow bore having a distal tip configured toreceive a hypodermic needle assembly and an open, often flanged proximalend configured to receive a dispensing plunger/piston. In preferredembodiment, the outside of the barrel is provided with graduatedmarkings indicating the volume of fluid in the syringe.

The distal tip or “needle hub” of a syringe barrel finding utility inthe context of the present invention is preferably threaded or taperedso as enable firm connection to a hypodermic needle assembly. Perhapsthe most well-known of these is the “Luer taper” or “Luer lock”, whichsimply twists the two together. Alternatively, the needle hub may takethe form of a “slip tip”, a small, friction-fit connection useful whenthe syringe is being connected to something not featuring a screw lockmechanism. Similar to this is the “catheter tip”, which is essentially aslip tip but longer and tapered, making it good for pushing into thingswhere there the plastic taper can form a tight seal.

Lyophilization methods of the present invention offer decreased cycletimes, a contributing factor being improved heat transfer to and fromthe product. An essential element of this method is a thermal blockformed of a suitable metallic material. Accordingly, the presentinvention refers interchangeably to a “block”, “thermal block”, and“heat block” fabricated from a heat conductive material and having aplurality of identical wells orderly arrayed about its top surface,wherein each of said wells is configured to receive a container carryingproduct to be lyophilized. In a preferred embodiment, the block isaluminum, chosen for its light weight and excellent thermal conductiveproperties.

Wells formed in the top surface of the block are designed anddimensioned to receive suitable containers of product to be lyophilized,such as a vial or a syringe barrel. In the context of the presentinvention, the wells are sized and shaped to closely accommodate theparticular container of choice. For example, in the exemplaryembodiments described in detail below, the containers take the form ofsyringe barrels having a substantially square cross-section, whereinsides are optionally bowed outward to form convex outer surfaces. Theassociated wells are analogously shaped and configured to causedeformation of the syringe barrel in a manner that causes the outerwalls of the barrel to be compressed against the inner walls of the wellso as to create close contact and optimal conditions for heatconduction. However, one of skill in the art will recognize that theprinciples taught herein are applicable to syringe barrel shapes otherthan substantially square. For instance, the shape may be rectangular, aregular or irregular polygon, oval or oblong, circular, or may have anirregular curvilinear profile. So long as the shape allows deformationwhen inserted into a suitably configured well so as to createsubstantial intimate contact between surfaces of the barrel and of thewell, it falls within the scope of this invention.

In the methods of the present invention exemplified below, a pluralityof resilient polymeric syringe barrels, each of which having asubstantially square cross-section, are singularly introduced into acorresponding plurality of wells evenly arrayed about the top surface ofa metallic thermal block, wherein the wells are dimensioned in such away as to cause deformation of the syringe barrel and thereby createintimate contact between outer surfaces of the syringe barrel and wellsidewalls. Again, one of skill in the art will recognize that thecriticality lies less with the precise shape of the respectivecontainers and wells than with the close contact generated by theirconnection. Thus, regardless of shape, any lyophilization method inwhich a polymeric syringe barrel with a first cross-sectional shape isinserted into a well in a metallic block or plate with the well having asecond different shape that serves to create surface contact thatenhances thermal conductivity therethrough falls within the scope ofthis invention.

In the embodiments previously herein described and exemplified below,the product container is the barrel of a syringe. It will be understoodthat the container need not be a syringe but may be a vial or any othersuitable container formed of a suitable resilient polymeric materialsuch that, when the container is inserted into the thermal block, thewalls of the container deform so as to create intimate contact betweenouter surfaces of the container and the well into which it is inserted.Any such product container falls within the scope of the presentinvention.

In the context of the present invention, the terms “sealing member”,“sealing cap”, and “venting cap” are used interchangeably to refer tothe cap element designed to coordinate with the open proximal end of thesyringe barrel. When positioned in a first configuration in which thecap is partially inserted into the proximal end opening, the cap affordsan escape path for outgassing during the lyophilization process.However, when moved into a second configuration in which the cap isfully inserted into the proximal end of the syringe barrel, the cap actsto seal lyophilized product within the syringe barrel.

In the context of the present invention, the terms “subject” and“patient” are used interchangeably herein to refer to any animal (e.g.,a mammal), including, but not limited to, humans, non-human primates,canines, felines, rodents, and the like, which is to be the recipient ofa particular treatment. In preferred embodiments, the subject is ahuman, more preferably a patient in need of subcutaneous, intravenousand/or intramuscular pharmaceutical therapy.

Hereinafter, the present invention is described in more detail byreference to the Figures and Examples. However, the following materials,methods, figures, and examples only illustrate aspects of the inventionand are in no way intended to limit the scope of the present invention.As such, methods and materials similar or equivalent to those describedherein can be used in the practice or testing of the present invention.

EXAMPLES

A syringe barrel 100 of the present invention is depicted in FIGS. 1through 7 . Barrel 100 has an elongate mid-portion 106 with barrelflange 108 formed at its proximal end, and distal output portion 112 atits distal end. In preferred embodiments, output portion 112 is a Luerlock or Luer taper. Rim 110 extends proximally from the proximal surfaceof barrel flange 108. As best seen in FIG. 7 , the walls of barrelmid-portion 106 with outer surfaces 107 are not planar, but rather havea predetermined convex shape. Syringe barrel 100 is formed of aresiliently deformable polymeric material. In preferred embodiments, thematerial is polypropylene.

A cap 200 for removable mounting to the proximal end of syringe barrel100 is depicted in FIGS. 8 through 12 . Cap 200 has a proximal portion202 and a distal portion 204 wherein is formed distal recess 206 andslot 208. Circumferential groove 210 is formed in the distal surface ofproximal portion 202, groove 210 being configured to accept therein rim110 of syringe barrel 100.

Stopper 250, depicted in FIGS. 13 through 15 is configured for removableplacement in output portion 112 of syringe barrel 100. Stopper 250 has aproximal portion 252 and a distal portion 254. In a preferredembodiment, stopper 250 is a Luer cap.

FIGS. 16 through 22 depict syringe assembly 300. Barrel 100 has stopper250 removably placed in distal output portion 116 of barrel 100 to sealthe distal end of barrel 100. Cap 200 is removably mounted to barrel 100in a first, partially inserted position in which the proximal portion ofslot 208 of cap 200 is exposed so as to form a passage for gaseousoutflow from the interior of syringe barrel 100.

Syringe assembly as pictured in FIGS. 23 through 26 is identical toassembly 300 of FIGS. 16 through 22 except that cap 200 is fullyinserted so that slot 208 is fully covered, thereby isolating theinterior of syringe barrel 100 from the surrounding environment.

Hereafter, exemplary methods of the present invention for lyophilizationof a product are described.

In a first step of the method depicted in FIGS. 27 and 28 , a product 10to be lyophilized is placed in syringe barrel 100, with stopper 250removably inserted in distal portion 112. Referring now to FIGS. 29 and30 , in a second step of the method, cap 200 is inserted into syringebarrel 100 and positioned as depicted in FIGS. 18 through 22 , slot 208in cap 200 being exposed so as to provide an escape path for outgassingduring the lyophilization process.

A first embodiment of a block 420 formed in accordance with principlesof the present invention is depicted in FIGS. 31 through 33 . Analternate embodiment in which the wells 1404 of the inventive block 1420are more rounded in shape is depicted in FIG. 79 . With reference to theformer, block 420 has a first surface 402 in which are formed wells 404.The construct and function of block 420 will be now described withregard to a segment 400 of block 420 depicted in FIGS. 34 through 37wherein segment 400 is oriented so that wells 404 are vertical. Segment420 has a height 406 and wells 400 have a square shape of width andheight 410. Well 404 has side walls 408. For simplicity, hereinafterblock segment 400 will be referred to simply as “block” 400. It will beunderstood that this term refers to a segment of block 420 and isequally applicable to all well-containing segments of block 420.

In a third step of a lyophilization method of the present invention,syringe barrel 100 containing product 10 is inserted into block 400 asdepicted in FIGS. 38 through 41 . As best seen in FIG. 40 , mid-portion106 of syringe barrel 100 is tightly confined within well 404 of block400, the convex walls of mid-portion 106 (see FIG. 7 ) being deformed sothat outer surfaces 107 of mid-portion 106 of syringe barrel 100 arepressed tightly against inner surfaces 408 of well 404.

As discussed above, a close fit between the vessel containing theproduct and the well or other shaped cavity in a plate is necessary toachieve conductive heat transfer between the product and the plate.Moreover, it will be understood that conduction can only occur throughsurfaces that are in contact. If a vessel only closely conforms to thecavity in which it is placed, conduction will occur only in portionswherein the vessel and cavity are in contact. Voids between the vesseland the surrounding cavity effectively insulate the vessel since heattransfer must occur by radiation or convection. In the case ofradiation, the temperature difference between the vessel/product and thecavity is insufficient to cause effective cooling. Since thelyophilization process occurs in a vacuum, there is no medium presentfor convective cooling.

In the assemblies and methods of the present invention, there isintimate contact between outer surfaces 107 of syringe barrel 100 andsidewalls 408 of well 400 so as to allow conductive heat transferthrough virtually all walls of mid-portion 106 of syringe barrel 100.

In a fourth step in a lyophilization method of the present inventiondepicted in FIGS. 42 and 43 , block 400 and syringe assembly 300contained therein are reoriented to a horizontal position. Duringlyophilization, water is removed by sublimation, a process that beginsat the free surface of the product and progresses downward until all ofthe product is sublimated. The time required to complete the process isdetermined by the vertical distance through which the sublimationprocess must progress, and the rate of heat transfer to and from product10. By reorienting block 400 and syringe assembly 300 to the horizontalposition, the distance through which sublimation must progress isdrastically reduced from what it was with block 400 and syringe assembly300 in the vertical position. Also, because portions of mid-portion 106of syringe barrel 100 containing product 10 have wall outer surfaces 107in contact with inner surfaces 408 of well 404, heat transfer is optimaland evenly distributed to product 10.

In FIG. 44 , sublimation of product 10 has been completed so as toproduce lyophilized product 20. Block 400 and syringe assembly 300contained therein are returned to a vertical orientation in a fifth stepof the method of the present invention depicted in FIG. 45 . In a sixthstep of the method, cap 200 is inserted fully into syringe barrel 100 asdepicted in FIGS. 46 and 47 , rim 110 of syringe barrel 100 beingpositioned within slot 210 of cap 200, and slot 208 of cap 200 beingcovered so as to seal lyophilized product 20 within syringe assembly300.

FIG. 48 depicts an ejector plate 520 that may be used to assist in theremoval of the plurality of syringes 300 from the wells of block 420(FIGS. 31 through 33 ). Ejector plate 520 has a planar base 502 fromwhich protrude vertical portions 504. Vertical portions 504 have formedin their top surface's recesses 506, recesses 506 being configured toaccommodate distal portions 114 of syringe barrel 100, and stopper 250positioned therein. FIGS. 49 through 51 depict a segment 500 of ejectorplate 520 containing a single vertical portion 504. Hereinafter thefunction of ejector plate 520 will be described using segment 500. Forsimplicity, segment 500 of ejector plate 520 will be referred to as“ejector 500” in the following descriptions. It will be understood thatdescriptions of the ejector functions so described are applicable to allsegments of ejector plate 520.

Block 400 with syringe assembly 300 therein may be positioned on ejector500 as depicted in FIGS. 52 through 55 . Moving block 400 downward asdepicted in FIGS. 56 through 58 causes syringe assembly 300 to bepartially dislodged from block 400 so as to allow easy manual removal ofsyringe assembly 300 from block 400.

FIGS. 59 and 60 depict lyophilized product 20 in sealed syringe assembly300 at the completion of lyophilization using methods and devices of thepresent invention.

In methods and devices previously herein described, at completion theproduct is contained in a syringe assembly sealed with a cap. Before useof the product, the cap must be removed and a diluent added to thesyringe for reconstitution of the lyophilized product. Thereafter, acombination of piston and plunger may be inserted into the syringe bodyand the medication may be administered to the patient. In other methodsof the present invention the lyophilized product is contained within asyringe wherein the piston component is already in place and providesthe proximal seal. This is advantageous as it minimizes steps requiredbefore administration of the product with their associated potential forcompromised product or wastage.

An exemplary method for producing lyophilized product in a syringe readyfor solubilization and administering to a patient is hereafterdescribed.

FIG. 61 depicts elements of a system for lyophilizing product in asyringe assembly wherein at completion the product is contained in asyringe with plunger, ready for solubilization and administering to apatient. A plurality of syringe barrels 600 are inserted into block 420.Thereafter, gasket 460 with openings 462 and plate 470 with openings 472are affixed to block 420 by a suitable securing method, not shown.Hereafter details of the method will be described as previously doneusing block segment 400 and syringe body 600 positioned therein. Syringebarrel 600 is identical to syringe barrel 100 (FIGS. 1 through 7 ) inall aspects of form and function except as specifically subsequentlyspecified, namely rim 110 is eliminated. FIGS. 62 through 64 depict afirst step in a lyophilization method of the present embodiment whereinsyringe barrel 600 containing product 10 for lyophilization is insertedinto block 400. In a second step, gasket 460 and plate 470 are affixedto block 400 wherein aligned openings 462 and 472 are offset from theaxis of barrel 600 as shown in FIG. 66 . Block 400 with syringe barrel600 positioned therein and plate 470 and gasket 460 affixed thereto isreoriented to a horizontal position as depicted in FIG. 67 in a thirdstep of the method. Aligned openings 462 and 472 provide a path forventing during sublimation of product 10. In FIG. 68 , sublimation iscomplete and liquid product 10 has become lyophilized product 20.Thereafter, in a fourth step of the method, block 400 with syringebarrel 600 containing product 20 and gasket 460 and plate 470 affixedthereto is reoriented to the vertical position as depicted in FIG. 69 .Plate 470 and gasket 460 are then removed in a fifth step of the methodafter which block 400, syringe barrel 600 and product 20 are as shown inFIG. 70 . Syringe plunger 630 with piston seal 640 is then assembled tosyringe body 600 as depicted in FIGS. 71 and 72 in a sixth step of themethod to create syringe assembly 700. Plunger 630 is inserted untilseal 640 of plunger 630 effectively seals off the interior of syringebarrel 600 and product 20 contained therein from outside contamination.Syringe assembly 600 is then partially ejected from block 400 usingejector 500 in the manner previously herein described (FIGS. 73 and 74 )after which sealed syringe assembly 600 is removed manually (seventhstep). Thereafter syringe assembly 700 is reoriented as depicted inFIGS. 75 and 76 and stopper 250 is removed. Plunger 630 is then advancedto remove excess air from syringe assembly 700, after which stopper 250is reinserted. FIGS. 77 and 78 depict lyophilized product 20 in syringeassembly 700 ready for the addition of a diluent and administration to apatient. Because product 20 is lyophilized, special storage conditionsare not required.

INDUSTRIAL APPLICABILITY

As discussed above, lyophilization is ubiquitous in the chemical,pharmaceutical, and food industries. However, there is an ongoing needin the art to improve the efficiency and economy of the lyophilizationprocess. The instant invention addresses this continuing need byproviding a readily scalable lyophilization assembly, apparatus andmethod that imparts a shorter lyophilization cycle timeline and affordsuniformity in all units of a lyophilization batch.

While the invention is herein described in detail and with reference tospecific embodiments thereof, it is to be understood that the foregoingdescription is exemplary and explanatory in nature and is intended toillustrate the invention and its preferred embodiments. Through routineexperimentation, one skilled in the art will readily recognize thatvarious changes and modifications can be made therein without departingfrom the spirit and scope of the invention. For example, this disclosureincludes and contemplates combinations with features and elements knownto the average artisan in the art. Thus, the novel embodiments,features, and elements that have been disclosed may also be combinedwith any conventional features or elements to form a distinct inventionas defined by the claims. Likewise, any feature or element of anyembodiment may also be combined with features or elements from otherinventions to form another distinct invention as defined by the claims.Therefore, it will be understood that any of the features shown and/ordiscussed in the present disclosure may be implemented singularly or inany suitable combination.

Other advantages and features will become apparent from the claims filedhereafter, with the scope of such claims to be determined by theirreasonable equivalents, as would be understood by those skilled in theart. Thus, the invention is intended to be defined not by the abovedescription, but by the following claims and their equivalents.

All publications, patent applications, patents and other referencesmentioned herein are incorporated by reference in their entirety.However, nothing herein should be construed as an admission that theinvention is not entitled to antedate such disclosure by virtue of priorinvention.

1. A lyophilization syringe configured for both the in situlyophilization of an initial product and the reconstitution anddispensing of said product in lyophilized form, said syringe comprising:a. an elongate central barrel characterized by (i) a plurality ofdistinct, resiliently deformable lateral walls joined together to definean exterior surface and a hollow interior bore configured to retain bothsaid initial product and said product in lyophilized forms, (ii) an opendistal tip configured to engage a hypodermic needle assembly; and (iii)an open proximal end configured to receive a sealing piston anddispensing plunger; b. wherein said central barrel has a non-circularcross-section; c. further wherein insertion of said syringe into a wellarranged on a top side of a thermal lyophilization block made from asingle piece of heat conductive material that is sized and shaped toclosely accommodate said syringe causes said lateral walls to deform andsaid exterior surface to be compressed into substantial intimate contactwith an inner wall of said well.
 2. The lyophilization syringe of claim1, wherein central barrel has a substantially square cross-section. 3.The lyophilization syringe of claim 1, wherein central barrel has anirregular curvilinear cross-section.
 4. The lyophilization syringe ofclaim 3, wherein said central barrel comprises four of said deformablelateral walls, each of which bows outward to define a convex exteriorsurface.
 5. The lyophilization syringe of claim 1, wherein the openproximal end of said central barrel is further characterized by a wideradial flange and the open distal tip is sealed by a distal stopper. 6.The lyophilization syringe of claim 5, wherein said open distal tipcomprises a Luer taper and said distal stopper comprises a Luer cap. 7.The lyophilization syringe of claim 1, wherein said syringe furthercomprises a venting cap removably mounted to the open proximal end,whereby, when said cap is partially inserted into said open proximalend, a passage for gaseous outflow from the central barrel is formed,thereby providing an escape path for outgassing during said in situlyophilization, further wherein said passage is closed when said cap isfully inserted into said open proximal end, such that said lyophilizedproduct is sealed within said central barrel.
 8. The lyophilizationsyringe of claim 1, wherein said syringe further comprises a sealingpiston and dispensing plunger disposed in said central barrel via saidopen proximal end.